Epstein-Barr Virus-associated lymphoproliferative disorders (EBV-LPDs) are a significant cause of morbidity and mortality for solid organ transplant recipients, hematopoietic stem cell transplant recipients, and other immunocompromised patients. Different therapies have been developed to treat EBV-LPDs, such as chemotherapy, combination chemotherapy, radiation therapy, therapy with rituximab (an anti-CD20 monoclonal antibody), and cellular immunotherapy (see, for example, Elstrom et al., 2006, Am J Transplant 6:569-576; Haque et al, 2001, Transplantation 72:1399-1402; Haque et al, 2002, Lancet 360:435-442; Gandhi et al, 2007, American Journal of Transplantation 7:1293-1299; and Doubrovina, E., et al., Blood, 2012. 119: 2644-2656). In situations where a first-line therapy has failed, later lines of therapy are often attempted. For example, for many SOT recipients, especially those with low grade disease, the first-line of treatment is decreasing dosage of immunosuppressant given to the patient. Several authors have reported efficacy of single agent rituximab in patients who failed to respond to reduction in immunosuppressant dosage (see, for example, Webber et al, 2004, Blood 104: Abstract 746; and Messahel et al, 2006, Leuk Lymphoma 47:2584-2589). If patients relapse after responding to rituximab or fail to respond to rituximab, there is no consensus in terms of whether re-treating with single agent rituximab is worthwhile and many centers will proceed to combination chemotherapy. The Children's Oncology Group recently completed a trial of low dose cyclophosphamide, steroids and rituximab with 2 year EFS (event free survival) of 71% and OS (overall survival) of 83% (Gross et al., 2012, Am J Transplant 12:3069-3075). In adult patients the treatment is more varied and includes R-CHOP (a therapy regimen with cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab) or DA-EPOCH (Dose-Adjusted EPOCH, which is a therapy regimen with etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin). In patients with CNS (central nervous system) involvement of EBV-LPD, regimens include intrathecal rituximab, radiation or high dose methotrexate alone for CNS only disease, or in combination for systemic and CNS disease.
EBV-LPDs resistant to a previous therapy that has shown to be effective clinically (for example, combination chemotherapy, radiation therapy, or therapy with rituximab) are harder to treat. The greater the degree of efficacy the previous therapy has shown to demonstrate clinically, and the more therapies the patient has failed, the greater the expectation of difficulty in achieving successful treatment by a later-line therapy. An EBV-LPD that is resistant to a previous therapy is usually more aggressive. This is especially true when the previous therapy is chemotherapy or radiation therapy, which often leads to or selects for mutated tumor cells, resulting in a much more aggressive disease. First-line therapies are usually selected based on their desirable combination of safety and efficacy, while later lines of therapy are usually considered less desirable in terms of their safety and/or efficacy profiles. Thus, there is a need for methods of treating EBV-LPD in patients who have failed combination chemotherapy and/or radiation therapy that have desirable safety and efficacy profiles.
Citation of a reference herein shall not be construed as an admission that such is prior art to the present disclosure.